The present invention relates to methods of treating patients having immunodeficiency virus type-1 (xe2x80x9cHIV-1xe2x80x9d) infections by administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a CCR5 antagonist sufficient to lower HIV-1-RNA.
The global health crisis caused by Human Immunodeficiency Virus-1 (xe2x80x9cHIV-1xe2x80x9d), the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus.
It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to the use of small molecules which are CCR5 antagonists in assoiation with pegylated interferon-alfa to treat patients having HIV-1 infections.
A-M. Vandamme et al., Antiviral Chemistry and Chemotherapy, 9:187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (xe2x80x9cHAARTxe2x80x9d); HAART involves various combinations of nucleoside reverse transcriptase inhibitors (xe2x80x9cNRTIxe2x80x9d), non-nucleoside reverse transcriptase inhibitors (xe2x80x9cNNRTIxe2x80x9d) and HIV protease inhibitors (xe2x80x9cPIxe2x80x9d). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
The present invention provides a method of treating patients having HIV-1 infections which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a CCR5 antagonist sufficient to lower HIV-1-RNA plasma levels.
The present invention also provides a method of treating patients having HIV-1 infections which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a CCR5 antagonist represented by the structural formula I or II or III or IV 
or a pharmaceutically acceptable salt of I or II or III or IV, sufficient to lower HIV-1-RNA plasma levels;
wherein in the CCR5 antagonist compounds represented by structural formula I: 
X is xe2x80x94C(R13)2xe2x80x94, xe2x80x94C(R13)(R19)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N((C1-C6)alkyl)-, 
R is R6-phenyl, R6-pyridyl, R6-thiophenyl or R6-naphthyl;
R1 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R2 is R7, R8, R9-phenyl; R7, R8, R9-substituted 6-membered heteroaryl;
R7, R8, R9-substituted 6-membered heteroaryl N-oxide;
R10, R11-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl 
xe2x80x83or 
R3 is R6-phenyl, R6-heteroaryl or R6-naphthyl;
R4 is hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl, cyclopropylmethyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)xe2x80x94NH(C1-C6)alkyl or xe2x80x94CH2C(O)xe2x80x94N((C1-C6)alkyl)2;
R5 and R11 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CH3SO2xe2x80x94, CF3SO2xe2x80x94, R14-phenyl, R14-benzyl, CH3C(xe2x95x90NOCH3)xe2x80x94, CH3C(xe2x95x90NOCH2CH3)xe2x80x94, 
xe2x80x83xe2x80x94NH2, xe2x80x94NHCOCF3, xe2x80x94NHCONH(C1-C6 alkyl), xe2x80x94NHCO(C1-C6 alkyl), xe2x80x94NHSO2(C1-C6 alkyl), 5-membered heteroaryl and 
xe2x80x83wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R7 and R8 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR20R21, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, and xe2x80x94OCF3;
R9 is R7, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR20, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R20)CONR21R22, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C10)-cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6)alkyl, C3-C10 cycloalkyl, xe2x80x94SR23, xe2x80x94SOR23, xe2x80x94SO2R23, xe2x80x94SO2NH(C1-C6 alkyl), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CON R20R21, xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R20, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R10 is (C1-C6)alkyl, xe2x80x94NH2 or R12-phenyl;
R12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R20, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R13, R14, R15 and R16 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl;
R17 and R18 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R17 and R18 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R19 is R6-phenyl, R6-heteroaryl, R6-naphthyl, C3-C10 cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
R20, R21 and R22 are independently selected from the group consisting of H and C1-C6 alkyl; and
R23 is C1-C6 alkyl or phenyl;
and wherein in the CCR5 antagonist compounds represented by the structural formula II: 
or a pharmaceutically acceptable salt thereof, wherein
(1)
Xa is xe2x80x94C(R13)2xe2x80x94, xe2x80x94C(R13)(R19)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N((C1-C6)alkyl)-, 
Ra is R6a-phenyl, R6a-pyridyl, R6a-thiophenyl or R6-naphthyl;
R1 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R2 is R7, R8, R9-phenyl; R7, R8, R9-substituted 6-membered heteroaryl;
R7, R8, R9-substituted 6-membered heteroaryl N-oxide;
R10, R11-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl 
xe2x80x83or 
xe2x80x83R3 is R10-phenyl, pyridyl, pyrimidyl, pyrazinyl or thiazolyl;
R4 is hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl, cyclopropylmethyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)xe2x80x94NH(C1-C6)alkyl or xe2x80x94CH2C(O)xe2x80x94N((C1-C6)alkyl)2;
R5 and R11 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6a is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, xe2x80x94CF3, CF3Oxe2x80x94, xe2x80x94CN, xe2x80x94CF3SO2xe2x80x94, R12-phenyl, xe2x80x94NHCOCF3, 5-membered heteroaryl and 
xe2x80x83wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R6 is independently selected from the group consisting of R6a and CH3SO2xe2x80x94;
R7 and R8 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR20R21, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, and xe2x80x94OCF3;
R9 is R7, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR20, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R20)CONR21R22, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C10)-cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6)alkyl, C3-C10 cycloalkyl, xe2x80x94SR23, xe2x80x94SOR23, xe2x80x94SO2R23, xe2x80x94SO2NH(C1-C6 alkyl), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CON R20R21, xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R20, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R10 is (C1-C6)alkyl, xe2x80x94NH2 or R12-phenyl;
R12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R20, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R13, R14, R15 and R16 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl;
R17 and R18 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R17 and R18 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R19 is R6-phenyl, R6-heteroaryl, R6-naphthyl, C3-C10 cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
R20, R21 and R22 are independently selected from the group consisting of H and C1-C6 alkyl; and
R23 is C1-C6 alkyl or phenyl; or
(2):
Xa is xe2x80x94C(R13)(R19)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N((C1-C6)alkyl)-, 
Ra is R6b-phenyl, R6b-pyridyl or R6b-thiophenyl;
R4a is fluoro-C1-C6 alkyl, cyclopropylmethyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)xe2x80x94NHxe2x80x94(C1-C6)alkyl or xe2x80x94CH2C(O)xe2x80x94N((C1-C6)alkyl)2;
R6b is CH3SO2xe2x80x94; and
R1, R2, R3, R5, R14, R15, R16 and R19 are as defined in II(1);
and wherein in the CCR5 antagonist compounds represented by the structural formula III: 
R is R8-phenyl, R8-pyridyl, R8-thiophenyl or R8-naphthyl;
R1 is hydrogen or C1-C6 alkyl;
R2 is R9, R10, R11-phenyl; R9, R10, R11-substituted 6-membered heteroaryl; R9, R10, R11-substituted 6-membered heteroaryl N-oxide;
R12, R13-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl 
xe2x80x83or 
xe2x80x83R3 is hydrogen, C1-C6 alkyl, (C1-C6)alkoxy(C1-C6)alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C6)alkyl, R8-phenyl, R8-phenyl(C1-C6)alkyl, R8-naphthyl, R8-naphthyl(C1-C6)alkyl, R8-heteroaryl or R8-heteroaryl(C1-C6)alkyl;
R4, R5, R7 and R13 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CH3SO2xe2x80x94, CF3SO2xe2x80x94, R14-phenyl, R14-benzyl, CH3C(xe2x95x90NOCH3), CH3C(xe2x95x90NOCH2CH3), 
xe2x80x83xe2x80x94NH2, xe2x80x94NHCOCF3, xe2x80x94NHCONH(C1-C6 alkyl), xe2x80x94NHCO(C1-C6 alkyl), xe2x80x94NHSO2(C1-C6 alkyl), 5-membered heteroaryl and 
xe2x80x83wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R9 and R10 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR17R18, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, xe2x80x94OCF3 and xe2x80x94Si(CH3)3;
R11 is R9, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR17, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R17)CONR18R19, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C1)cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6)alkyl, C3C10 cycloalkyl, xe2x80x94SR20, xe2x80x94SOR20, xe2x80x94SO2R20, xe2x80x94SO2NH(C1-C6 alkyl), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CON R17R18, xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R17, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R12 is (C1-C6)alkyl, xe2x80x94NH2 or R14-phenyl;
R14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R17, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R15 and R16 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R15 and R16 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R17, R18 and R19 are independently selected from the group consisting of H and C1-C6 alkyl; and
R20 is C1-C6 alkyl or phenyl;
and wherein in the CCR5 antagopnist compounds represented by the structural formula IV: 
or a pharmaceutically acceptable salt thereof, wherein
(1)
Ra is R8a-phenyl, R8b-pyridyl, R8b-thiophenyl or R8-naphthyl;
R1 is hydrogen or C1-C6 alkyl;
R2 is R9, R10, R11-phenyl; R9, R10, R11-substituted 6-membered heteroaryl; R9, R10, R11-substituted 6-membered heteroaryl N-oxide;
R12, R13-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl, 
xe2x80x83or 
xe2x80x83R3 is hydrogen, C1-C6 alkyl, (C1-C6)alkoxy(C1-C6)alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C6)alkyl, R8-phenyl, R8-phenyl(C1-C6)alkyl, R8-naphthyl, R8-naphthyl(C1-C6)alkyl, R8-heteroaryl or R8-heteroaryl(C1-C6)alkyl;
R4, R5, R7 and R13 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CH3SO2xe2x80x94, CF3SO2xe2x80x94, R14-phenyl, R14-benzyl, CH3C(xe2x95x90NOCH3), CH3C(xe2x95x90NOCH2CH3), 
xe2x80x83xe2x80x94NH2, xe2x80x94NHCOCF3, xe2x80x94NHCONH(C1-C6 alkyl), xe2x80x94NHCO(C1-C6 alkyl), xe2x80x94NHSO2(C1-C6 alkyl), 5-membered heteroaryl and 
xe2x80x83wherein Xb is a xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R8a is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CF3SO2xe2x80x94, R14-benzyl, CH3C(xe2x95x90NOCH3), CH3C(xe2x95x90NOCH2CH3), 
xe2x80x94NHCOCF3, 5-membered heteroaryl and 
xe2x80x83wherein Xb is as defined above;
R8b is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CF3SO2xe2x80x94, R14-benzyl, CH3C(xe2x95x90NOCH3), CH3C(xe2x95x90NOCH2CH3), xe2x80x94NHCOCF3, 5-membered heteroaryl and 
xe2x80x83wherein Xb is as defined above;
R9 and R10 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR17R18, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, xe2x80x94OCF, and xe2x80x94Si(CH3)3;
R11 is R9, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR17, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R17)CONR18R19, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C1)cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6)alkyl, C3-C10 cycloalkyl, xe2x80x94SR20, xe2x80x94SOR20, xe2x80x94SO2R20, xe2x80x94SO2NH(C1-C6 alkyl), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CONR17R18, xe2x80x94CON(CH2xe2x80x94Oxe2x80x94CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R17, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R12 is (C1-C6)alkyl, xe2x80x94NH2 or R14-phenyl;
R14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R17, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R15 and R16 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R15 and R16 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R17, R18 and R19 are independently selected from the group consisting of H and C1-C6 alkyl; and
R20 is C1-C6 alkyl or phenyl; or
(2)
Ra is R8-phenyl, R8-pyridyl or R8-thiophenyl;
R2 is fluorenyl, diphenylmethyl, 
xe2x80x83or 
xe2x80x83and R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are as defined in IV(1).
Preferred are compounds of formula I wherein R is R6-phenyl, especially wherein R6 is a single substituent, and especially wherein the R6 substituent is in the 4-position. Also preferred are compounds of formula I wherein R13, R14, R15 and R16 are each hydrogen or methyl, especially hydrogen. Also preferred are compounds of formula I wherein X is xe2x80x94CHOR3, xe2x80x94C(R13)(R19)xe2x80x94 or xe2x80x94C(xe2x95x90NOR4)xe2x80x94; a preferred definition for R3 is pyridyl, especially 2-pyridyl, a preferred definition for R4 is (C1-C6)alkyl, especially methyl, ethyl or isopropyl, a preferred definition for R13 is hydrogen, and a preferred definition for R19 is R6-phenyl. For compounds of formula I, R1 is preferably (C1-C6)alkyl, especially methyl.
In compounds of formula I, R2 is preferably R7, R8, R9-phenyl, R7, R8, R9-pyridyl or an N-oxide thereof, or R7, R8, R9-pyrimidyl. When R2 is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R7 and R8 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R9 substituent can be attached to any of the remaining unsubstituted carbon ring members, for example as shown in the following structures: 
Preferred R7 and R8 substituents are: (C1-C6)alkyl, especially methyl; halogen, especially chloro; and xe2x80x94NH2. A preferred R9 substituent is hydrogen.
Preferred are compounds of formula II(1) wherein Ra is R6a-phenyl, especially wherein R6a is a single substituent, and especially wherein the R6a substituent is in the 4-position. Also preferred are compounds of formula II(1) wherein Xa is xe2x80x94CHOR3, xe2x80x94C(R13)(R19)xe2x80x94 or xe2x80x94C(xe2x95x90NOR4)xe2x80x94; a preferred definition for R3 is pyridyl, especially 2-pyridyl, a preferred definition for R4 is (C1-C6)alkyl, especially methyl, ethyl or isopropyl, a preferred definition for R13 is hydrogen, and a preferred definition for R19 is R6-phenyl. For compounds of formula II(1), R1 is preferably (C1-C6)alkyl, especially methyl. Also for compounds of formula II(1), R14, R15 and R16 are preferably hydrogen.
Preferred are compounds of formula II(2) wherein Ra is R6b-phenyl, especially wherein R6b is a single substituent, and especially wherein the R6b substituent is in the 4-position. Also preferred are compounds of formula II(2) wherein Xa is xe2x80x94CHOR3, xe2x80x94C(R13)(R19)xe2x80x94 or xe2x80x94C(xe2x95x90NOR4a)xe2x80x94; a preferred definition for R3 is pyridyl, especially 2-pyridyl, preferred definitions for R4a are cyclopropylmethyl and trifluoroethyl, a preferred definition for R13 is hydrogen, and a preferred definition for R19 is R6-phenyl. For compounds of formula II(2), R1 is preferably (C1-C6)alkyl, especially methyl. Also for compounds of formula II(2), R14, R15 and R16 are preferably hydrogen.
In compounds of formula II(1) and (2), R2 is preferably R7, R8, R9-phenyl; R7, R8, R9-pyridyl or an N-oxide thereof; or R7, R8, R9-pyrimidyl. When R2 is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R7 and R8 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R9 substituent can be attached to any of the remaining unsubstituted carbon ring members as shown above for compounds of formula I. Preferred R7 and R8 substituents for compounds of formula II are: (C1-C6)alkyl, especially methyl; halogen, especially chloro; and xe2x80x94NH2; a preferred R9 substituent is hydrogen.
Preferred are compounds of formula III wherein R is R8-phenyl or R8-naphthyl, especially wherein R8 is a single substituent, and especially wherein the R8 substituent is in the 4-position. For R8-phenyl, preferred R8 substituents are xe2x80x94CF3, xe2x80x94OCF3, CH3SO2xe2x80x94, CH3COxe2x80x94, CH3C(xe2x95x90NOCH3)xe2x80x94, Br and I. For R8-naphthyl, R8 is preferably C1-C6 alkoxy. Also preferred are compounds of formula III wherein R3 is hydrogen, (C1-C6) alkyl, R8-phenyl. R8-benzyl or R8-pyridyl; more preferred definitions for R3 are methyl, ethyl, phenyl, benzyl and pyridyl. R1 is preferably hydrogen. For compounds of formula III, R6 is preferably hydrogen or methyl, especially methyl. R4 is preferably methyl; R5 and R7 are each preferably hydrogen.
In compounds of formula III, R2 is preferably R9, R10, R11-phenyl, R9, R10, R11-pyridyl or an N-oxide thereof, or R9, R10, R11-pyrimidyl. When R2 is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R9 and R10 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R11 substituent can be attached to any of the remaining unsubstituted carbon ring members, for example as shown in the following structures: 
Preferred R9 and R10 substituents are: (C1-C6)alkyl, especially methyl; halogen, especially chloro or bromo, xe2x80x94OH and xe2x80x94NH2. When R2 is phenyl, R11 is preferably hydrogen or xe2x80x94OH; when R2 is pyridyl, R11 is preferably hydrogen; and when R2 is pyrimidyl, R11 is preferably hydrogen, methyl or phenyl. Examples of particularly preferred R2 groups are as follows: 
Preferred compounds of formula IV are those defined in (1).
More preferred are those of formula IV(1) wherein Ra is R8a-phenyl or R8-naphthyl, wherein R8a is xe2x80x94CF3, CF3Oxe2x80x94 or halogen and R8 is C1-C6 alkoxy. The R8a or R8 substituent is preferably a single substituent; it is especially preferred that the R8a or R8 substituent is in the 4-position. Also preferred are compounds of formula IV(1) wherein R3 is hydrogen, (C1-C6) alkyl, R8-phenyl. R8-benzyl or R8-pyridyl; more preferred definitions for R3 are methyl, ethyl, phenyl, benzyl and pyridyl. R1 is preferably hydrogen. For compounds of formula IV(1), R6 is preferably hydrogen or methyl, especially methyl. R4 is preferably methyl; R5 and R7 are each preferably hydrogen.
R2 in formula IV(1) is preferably as defined for formula III, i.e., R9, R10, R11-phenyl, R9, R10, R11-pyridyl or an N-oxide thereof, or R9, R10, R11-pyrimidyl, wherein the R9, R10, R11-substitution is as defined above for preferred compounds of formula III.
The present invention also provides a method of treating patients co-infected with HIV-1 and HCV which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of ribavirin and a therapeutically effective amount of HAART and a therapeutically effective amount of a CCR5 antagonist represented by the structural formula I or II or III or IV: 
or a pharmaceutical salt of a compound of the formula I or II or III or IV;
sufficient to lower HIV-1-RNA and HCV-RNA plasma levels.
wherein X, R, and R1 to R16 are as defined in formula I; and
wherein X, Ra, and R1 to R16 are as defined in formula II(1) and II(2) and
wherein R, and R1 to R17 are as defined in formula III; and
wherein Ra, and R1 to R17 are as defined in formula IV.
The present invention also provides a method of treating pediatric patients having HIV-1 infections which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of HAART and a therapeutically effective amount of a CCR5 antagonist represented by the structural formula I or II or III or IV: 
or a pharmaceutical salt of compounds I or II;
sufficient to lower HIV-1-RNA plasma levels.
wherein X, R, and R1 to R16 are as defined in I; and
wherein Xa, Ra, and R1 to R16 are as defined in II(1) and II(2);
wherein R, and R1 to R17 are as defined in formula III; and
wherein Ra, and R1 to R17 are as defined in formula IV.